Amino derivatives of 4h-pyran-4-ones



United States, Patent 2,907,773 QAMINO DERIVATIVES OF 4H-PYRAN-4-ONESCarl Peter Krimmel, Mundelein, Ill., assignor to G. D. Searle & C0,,Chicago, 11]., a corporation of Delaware No Drawing. Application October2,1957 Serial No. 687,609

8 Claims. (Cl. 260--345.9)

The present inventionis concerned with basic derivatives of4H-pyran-4-one and with non-toxic salts thereof. More particularly, itis concerned with compounds which, in the; forms of free bases, can berepresented by the structural formula In this formula.v X, can representchlorine or a hydroxyl group. The. terms R and R represent lower alkylradi- (cal's, such as methyl, ethyl, propyl, butyl, amyl, hexyl,

lieptyl, octyl, and branched-chain isomers thereof.

Suitable starting materials for the manufacture of compositions of.this. invention are compounds corresponding to the formula alkylamine,or with aqueous formaldehyde, a dialkylamine and a mineral acid,condensation reactions take place with the formation of salts of thisinvention; The net effect of thecondensation reactions is theintroduction of a dialkylaminomethyl group at position 6 of the pyranring. Thus, by heating a mixture comprising kojic acid, aqueousformaldehyde, and dimethylamine hydrochloride and suitably containing aslight excess of hydrochloric acid, followed by inducing crystallizationin the cooled reaction-mixture, the compound obtained is 2-hydroxymethyl5 hydroxy-6-dimethylaminomethyl-4H-pyran-4- .onghydrochloride. Thiscompound and analogous compounds of this invention afiord-adistinctcoloration upon treatment with ferric chloride in aqueoussolution, thereby indicating the survival of a free enolic groupin thereaction product. p

Upon neutralization of the initially-formed mineral acid salts, the freebases of this invention result. For

example, when a concentrated, aqueous solution of a hydrochloride istreated with approximately one molecular equivalent of potassiumcarbonate, and the mixture is evaporated until only a wet residueremains, the desired free. base is recovered by extraction withisopropyl alcohol.

The: organic bases of this inventionform non-toxic, acid-addition saltswith a variety of organicandinorganic .agents, as shown bymethyl-4Hrpyran-4-one.

\ Patented Oct. 6, 1959 acids. Such salts, formed by admixture oftheorganic free base with an acid, suitably in a neutral solvent, areformed with such acids as sulfuric, phosphoric, hydrochloric,hydrobromic, hydriodic sulfamic, citric, lactic, maleic, malic,succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic, andrelated acids. For purposes of this invention the free bases areequivalent to their nontoxic acid-addition salts.

The organic bases of this invention, being amphoteric agents, also formsalts with a variety of other bases. Such salts can be formed byadmixture of an organic free base of this invention with a relativelystrong base, in a neutral solvent; Suitablefor: the formation of saltsof this type are alkali metal hydroxides and alkaline earthmetalhydroxides such as"potassium hydroxide, sodium hydroxide andcalciumhydroxide. For purposes ofthis invention the free bases are,equivalent to such non-toxic salts formed by interaction of the enolichydroxyl group With a strong base.

. The compositions ofthe presentdnvention are easily manufacturedsubstances having substantial water solubility, and are of value invarious pharmacological applications. They are, in particular, cardiacstimulants effective in increasing the contractility of heart muscle.Upon their administration, increases in cardiac output and contractionamplitude are achieved. They also have hormonal properties. Thus, theyare anti-inflammatory their effectiveness in treating inflammation. ofthe iris. Likewise, they also resemble .cortisone and hydrocortisone inproducing a decrease in .vascular permeability, by increasing theresistance of the vascular wall to injury. 7 a t This invention willappear more fully from the ex amples which follow. These examples areset forth by way of illustration only and it will be understood that theinvention is not to be construed as limited in spirit or in scope by thedetails contained therein, as many modifications in materials andmethods will be apparent from this disclosure to those skilled in theart. In these examples temperatures are given in degrees centigrade C.)and quantities of materials in partsby weight.

Example I seed crystals of the hydrochloride of 2-hydroxymethyl-5hydroxy-6-dimethylaminomethyl-4H-pyran-4-one, as obtamed in Example 3.The crystalline precipitate which separates is collected on a filter,washed by suspension in 24 parts of cold, absolute ethanol, againcollected on a filter, and Washed on the absolute ethanol.

carbon and recrystallization from absolute ethanol there are obtainedwhite, water-soluble crystals of the hydrochloride of2-chloromethyl-5-hydroxy-6-dlimethylamino This compound melts withdecomposition to a red-brown, frothy liquid at about'l80- filter. with16 parts of cold,

C. The free base has the structural formula Upon decolorization withactivated .pyran--4-one. 145-'-148 C.

A solution of 4 parts of this hydrochloride in 10 parts 3 Example 2 Astirred mixture of 16 parts of 2-chlorome'thyl-5-hydroxy-4H-pyran-4-one, 30.8 parts of diethylamine hydrobromide, 16.5parts. of 36-38% formaldehyde and 0.4 part of concentrated hydrobromicacid is heated at about.90 -100 C. for 1 hour. Crystallization isinduced in the cooled reaction mixture, and the separated product iscollected on a filter and washed with cold, absolute ethanol. Thiscompound is the hydrobromide of 2 chloromethylhydroxy-6-diethylaminomethyl-4H- pyran-4-one. The free base has thestructural formula Example 3 A stirred mixture of 32.6 parts ofdimethylamine hydrochloride, 28.4 parts of kojic acid, 20 parts of36-38% formaldehyde and 1.2 parts of concentrated hydrochloric acid isheated under reflux for 3 hours. The clear, dark red-brown reactionmixture is cooled, and crystallization is induced by such means asrubbing the wall of the reaction vessel with a glass rod. Thecrystalline product which separates is collected on a filter and washedwith absolute ethanol. The product is then decolorized with activatedcarbon and recrystallized from a mixture of 20 parts of water and -160parts of ethanol. The compound thus obtained consists of white,water-soluble crystals of the hydrochloride of 2-hydroxymethyl-5-hydroxy 6 dimethylarninomethyl-4H-pyran-4-one which melt at about189-193 C. with decomposition to a red- 'brown liquid. The free basewhich results from neutralization with sodium carbonate or potassiumcarbonate has the structural formula Example4 A stirred mixture of 28.4parts of kojic acid, 43.8 parts of diethylamine hydrochloride, 35.0parts of 36-68% formaldehyde and 1.2 parts of concentrated hydrochloricacid is heated in an open vessel at about 90100 C. for

'4 hours. The evaporation which takes place during the tained seedcrystals are introduced. Additional crystallization is promoted byfurther dilution with ether, by stirring, and by rubbing the wall of thecontainer with a glass rod. When separation of the crystallineprecipitate is complete, it is collected on a filter and dried. Thisproduct is then decolorized with activated carbon and recrystallizedfrom isopropyl alcohol. The white, Watersoluble compound obtained is thehydrochloride of 2-hydroxymethyl 5 hydroxy 6 diethylaminomethyl 4H- Itmelts to an amber liquid at about of water is treated with 1 part ofpotassium carbonate. The mixture is stirred until gas evolution ceasesand a homogenous solution is obtained. Water is removed by evaporationor by vaporization under reduced pressure until only a wet residueremains. The residue is extracted with 40 parts of isopropyl alcohol,and the insoluble, inorganic compounds are removed by filtration. Thefiltrate is concentrated to a viscous, light-red,-thermolabile syrup byvaporization of the isopropyl alcohol at or below room temperature,suitably with the aid of a stream of air or nitrogen. The syrup isextracted with parts of warm benzene, and the solution is treated withactivated charcoal and filtered. The pale buficolored crystals whichseparate upon cooling are col: lected on 'avfilter. This free base,Z-hydroxymethyl-S- hydroxy-6-diethylaminomethyl-4H-pyran-4-one, gives ared coloration upon'treatment with ferric chloride in aqueous solution,and melts at about 9496 C. to a' red liquid. The structural formula isExample 5 A mixture of 28.4 parts of kojic acid, 20.2 parts ofdipropylamine, 17.0 parts of 36-38% formaldehyde and 25.0 parts ofconcentrated hydrochloric acid is stirred and heated at about 90-l00 C.for 4 hours. Seed crystals obtained by a conventional technique areintroduced into the cooled reaction mixture. When separation of 'theinsoluble product is complete, it is collected on a filter and washedwith cold isopropyl alcohol. For purification, a solution of this crudeproduct in a minimum quantity of hot isopropyl alcohol is diluted withabout 4 times its volume of hot butanone, and the mixture is cooled andallowed to stand until recrystallization is complete. The product thusobtained consists of white, water-soluble needles which melt to a clearorange liquid at about 156-159 C. This compound is the hydrochloride of2-hydroxymethyl-S-hydroxy-o-dipropylaminomethyl-4H-pyran-4 one. The freebase, obtained by neutralization with potassium carbonate, has thestructural formula (CHaCHzCHr)2NGH 0 CHrOH (lower alkyDzNCH i cruxwherein X'is a member of the class consisting of chlorine and thehydroxyl group.

2. A compound of the structural formula a V I (lower aIkyIMNCH L -oH,o1

3. Z-ChIoromethyl-S-hydroxy-G-dimethylaminomethyl- 4H-pyran-4-one.

m4. ,2 Chloromethyl-S-hydroxy-6-diethylaminomethyl- H- PY an4-one. r

5 6 '5. A compound of the structural formula 8.Z-Hydroxymethyl-S-hydroxy-G-dipropylaminomethylv o 4H-pyran-4-one.

H0 References Cited in the file of this patent l I a Spielman et al.: I.Am. Chem. Soc., vol. 69, pp. 2-908 (lower alkyDzNOH -0E,'0H and 2909(1947). l 0 Woods: J. Am. Chem. 800., vol. 68, p. 2744 (1946). :6.'Z-Hydroxymethyl-5-hydroxy-6-dimethylaminometh Elderfield: HeterocyclicCmpds., vol. 1, pp. 386 and yl-4H-pyran-4-one. 387, Wiley (1950).

7. 2-Hydroxymethy1-5-hydroxy-6-diethylaminomethyl- 10 4H-pyran-4-one.

1. A COMPOUND OF THE STRUCTURAL FORMULA